Process for preparing cyclopentanoperhydrophenanthrene derivatives



Patented Oct. 20, L953 S.i166)lRJPRIERBiARINGrGIECLDBENTANO-vBERHXDROBHENAALTIBENE DEBIVA'IWES Francisco Nefimaim, John 'Pataki, and

'Kaufmann,

Stephen Mexico *Oity, Mexico, ass'ignors-to Syntax S. A., Mexico City,;'Mexico, :a @corpora- -tion ufMexico 'Nofbrawing.

Application 0Qt0be l Q, 1.9.50, lserialjiNo. 193,021

N-Bromoaz nides or N-Bromoimides Hydrazine-Hydrate 200 0. Strong AlkaliIn the --above equations -R. may be hydrogen, an alkyl group such asmethyl, ethyl 0r propyl or aryl group such as benzyl or'allicyclic suchas cyclohexyl; R1 may be a :monoacyl group, 13116 residue of a fattyacid-such as aceticflzhe residue of a dibasic acid such as -succinic.orthe residue of an aromatic acid suchiasbenzoic; R2 may be hydrogen or anacyl group similar to R1.

The processaccording to the present invention maybe carried outby'dissolving the 3-monoaeylderivatives of'3a,12fl-dihydroxy-il-ketocholanic acid in a suitable organic solvent inadmixture withnwaterand thereafter adding a suitable IN bromo acid-amide-'or N bromo acid-imide =in slight molar excess, preferablyN-bromoacetamide ,or Nebrornosuccinimide, to fi 'q er with la ala t cacid.

Although -N-bromoacetamide or '-N-'bromosucnim i s th rr rre o zin aeenieth r brominated amides or 'imidesrnay be-used, -such asbromotoluenesulfonimide or 'brornophthalimidfi. The reaction mixture isthen allowed Lto stand atroom temperature for approximatelyfourjhoursfand wateris then added slowly topre cipitate the desired -.p.'.01 1ct, as for example, 3 hemisuccinoxy-ll,12=methy1- cholanic a idor other equivalent aacyl derivatives of the acid or esters thereof, isabove described.

,Ihereafter, .in accordance with the second at on ndi at d ters, thmE-Q1J !Q D919- duced may be dissolved in a suitable solvent, such asdiethylene glycol or triethylene glycol, suflicient glycol beingpreferably used so that a clear or nearly clear reaction mixture isobtained during the subsequent heating period, and hydrazine-hydrateadded thereto. Preferably an amount of 85 hydrazine-hydrate is used sothat the hydrazine-hydrate is in substantial excess, as

for example 3 mols or more. The reaction mixture is preferably firstrefluxed for a period of approximately one hour and thereafter asuitable strong alkali, preferably an alkali metal hydroxide such aspotassium or sodium hydroxide, is added and the mixture refluxed foranother period of time, as for example thirty minutes. Preferably suchan amount of alkali is used so that there will be about 10% of alkali tothe volume of glycol used. The reflux condenser is then removed and thesolution is kept boiling in an open vessel or with the use of a take-offadapter until the temperature has risen to approximately 200 C.Thereafter the reaction mixture is once again refluxed for a period oftime, as for example three hours, chilled and diluted with water. Uponacidification with a suitable acid the desired product3e-hydroxy-ll-keto-cholanic acid precipitates in good yield. Thecholanio acid thus produced may be further purified by recrystallizationfrom a suitable solvent such as methanol.

In place of the 3-acyl derivatives of the abovementioned cholanic acidor its esters the 3a-hydroxy derivatives may also be used. These may beprepared by acid or alkaline hydrolysis of the 7 product of the amide orimide oxidation as above described, or these last compounds may be pre--pared in other ways known in the art.

The following specific examples serve to illustrate but are not intendedto limit this invention:

Example I Example II Following the procedure of Example 1, 3a.-hemisuccinoxy-11-keto-12-hydroxy cholanic acid on treatment with 1.1mols of N-bromosuccinimide, yielded 3a-hemisuccinoxy-1Ll2 -diketocholanic acid, which crystallized from methanol in leaflets, meltingpoint 233-236 C.

Example III 10 grams of 3a-hemisuccinoxy-11,12-diketomethyl cholanate,of Example I, were dissolved in 100 cc. of warm diethylene-glycol and 10cc. of hydrazine-hydrate (85%) were added. After refluxing for one hour,10 grams of potassium hydroxide in 10 cc. of Water were added slowly andrefluxing was continued for thirty minutes. The reflux condenser wasremoved and the solution kept boiling in the open vessel until thetemperature was raised to about 200. After refluxing 3 hours at thistemperature, the mixture was chilled and diluted with about 400 cc. ofwater. On acidification, 3a-hydroxy-ll-keto cholanic acid wasprecipitated. Crystallization from methanol yielded prisms melting at212-21'l C.

4 Example IV 10 grams of 3e-hemisuccinoxy-11,12-diketocholanic acid ofExample II were treated as described in Example 111, yielding the same3a-hydroxy 11 keto-cholanic acid melting at 212- 21'7 C.

Example VI 10 grams of 3a-hydroxy-1Ll2-diketo cholanic acid were treatedas described in Example III, yielding the same3a-hydroxyll-keto-cholanic acid melting at 2l2217 C.

We claim:

1. A method for preparing 3a-hydroxy-11- keto-cholanic acid whichcomprises oxidizing a compound selected from the group consisting of3-mono-acyl derivatives of 3a-12fl-dlhYdl0XY-l1- keto-cholanic acid andesters thereof with an oxidizing agent selected from the classconsisting of N-bromo acid-amides and N-bromo acidimides to thecorresponding derivatives of 311-1137- droxy-11,12-diketo-cholanic acidand thereafter dissolving said last-mentioned cholanic acidderivativesin a solvent selected from the class consisting of diethyleneglycol and triethylene glycol and reducing by heating withhydrazine-hydrate in the presence of a strong alkali.

2. A method for preparing 3e-hydroxy-llketo-cholanic acid whichcomprises oxidizing 3a.- hemisuccinoxy-l1-keto-l2-hydroxymethyl-cholanate with an oxidizing agent selected from the classconsisting of N-bromo acid-amides and N- bromo acd-imides to produce3c-hBlI1lSllCClIlOXY- 11,12 diketo methyl cholanate and thereafterdissolving said last-mentioned cholanate in a solvent selected from theclass consisting of diethylene glycol and triethylene glycol andreducing by heating with hydrazine-hydrate in the presence of a strongalkali.

3. A method for preparing 3a-hydroxy-1lketo-cholanic acid whichcomprises oxidizing 3ahemisuccinoxy-ll-keto-l2-hydroxy-cholanic acidwith an oxidizing agent selected from the class consisting of N-bromoacid-amides and N-bromo acid-imides to produce 3a-hemisuccinoxy-1L12-diketo-cholanic acid and thereafter dissolving said last-mentionedcholanic acid in a solvent selected from the class consisting ofdiethylene glycol and triethylene glycol and reducing by heating withhydrazine-hydrate in the presence of a strong alkali.

FRANCISCO NETTMANN. JOHN PATAKI. STEPHEN KAUFMANN.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,397,656 Gallagher Apr. 2, 1946 2,403,683 Reichstein July 9,1946 2,447,325 Gallagher M Aug. 17, 1948 2,471,697 Minlon May 31, 1949OTHER REFERENCES Fieser et al., Natural Products Related toPhenanthrene, 3d Edition, pp. 409-410 (1949).

1. A METHOD FOR PREPARING 3A-HYDROXY-11KETO-CHOLANIC ACID WHICHCOMPRISES AXIDIZING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF3-MONO-ACYL DERIVATIVES OF 3A-12B-DIHYDROXY-11KETO-CHOLANIC ACID ANDESTERS THEREOF WITH AN OXIDIZING AGENT SELECTED FROM THE CLASSCONSISTING OF N-BROMO ACID-AMIDES AND N-BROMO ACIDIMIDES TO THECORRESPONDING DERIVATIVES OF 3A-HYDROXY-11,12-DIKETO-CHOLANIC ACID ANDTHEREAFTER DISSOLVING SAID LAST-MENTIONED CHOLANIC ACID DERIVATIVES IN ASOLVENT SELECTED FROM THE CLASS CONSISTING OF DIETHYLENE GLYCOL ANDTRIETHYLENE GLYCOL AND REDUCING BY HEATING WITH HYDRAZINE-HYDRATE IN THEPRESENCE OF A STRONG ALKALI.